MIRD pamphlet No. 20: the effect of model assumptions on kidney dosimetry and response--implications for radionuclide therapy.
Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose-response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys.


METHODS
The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity.


RESULTS
Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and (166)Ho-phosphonate clinical investigations.


CONCLUSIONS
Radionuclide therapy dose-response data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.
Wessels
Barry W
BW
Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. barry.wesseks@uhhospitals.org
Konijnenberg
Mark W
MW
Dale
Roger G
RG
Breitz
Hazel B
HB
Cremonesi
Marta
M
Meredith
Ruby F
RF
Green
Alan J
AJ
Bouchet
Lionel G
LG
Brill
A Bertrand
AB
Bolch
Wesley E
WE
Sgouros
George
G
Thomas
Stephen R
SR
D000818:Animals; D004307:Dose-Response Relationship, Radiation; D007668:Kidney / Q000378:metabolism / Q000528:radiation effects*; D007674:Kidney Diseases / Q000628:therapy*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011829:Radiation Dosage; D011874:Radiometry / Q000379:methods*; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D011878:Radiotherapy / Q000009:adverse effects / Q000379:methods*; D051381:Rats
D019275:Radiopharmaceuticals